1. Technical Field of the Invention
The present invention relates to compositions for topical administration, and their applications as cosmetic or pharmaceutical products, such compositions being particularly useful for the treatment of acne.
2. Description of Background and/or Related and/or Prior Art
Acne is a frequent multifactorial pathology which affects skin rich in sebaceous glands (face, scalpular region, arms and intertriginous regions). It is the most frequent of the dermatoses. The following five pathogenic factors play a decisive role in the constitution of acne:
1. genetic predisposition;
2. overproduction of sebum (seborrhoea);
3. androgens;
4. follicular keratinization disorders (comedogenesis); and
5. bacterial colonization and inflammatory factors.
There are several forms of acne, which all have in common the impairment of the pilosebaceous follicles. There may be mentioned in particular acne conglobata, acne keloid of the nape of the neck, acne medicamentosa, recurrent miliary acne, acne necrotica, acne neonatorum, premenstrual acne, occupational acne, acne rosacea, senile acne, solar acne and acne vulgaris.
Acne vulgaris, also called polymorphic juvenile acne, is the most common. It comprises four stages, but passage through all the stages is not obligatory:
Stage 1 corresponds to comedonal acne characterized by a large number of open and/or closed comedones, and of microcysts.
Stage 2, or papulopustular acne, is of mild to moderate seriousness. It is characterized by the presence of open and/or closed comedones, of microcysts, but also of red papules and of pustules. It affects mainly the face and leaves few scars.
Stage 3, or papulocomedonal acne, is more serious and extends to the back, to the thorax and to the shoulders. It is accompanied by a larger number of scars.
Stage 4, or nod ulocystic acne, is accompanied by numerous scars. It has nodules as well as large purplish and painful pustules.
The various forms of acne described above may be treated with active agents such as anti-seborrhoeic agents and anti-infective agents, for example benzoyl peroxide (in particular the product Eclaran® marketed by Pierre Fabre), with retinoids such as tretinoin (in particular the product Retacnyl® marketed by Galderma) and isotretinoin (the product Roaccutane® marketed by Laboratoires Roche), or with naphthoic acid derivatives. Naphthoic acid derivatives such as in particular 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, commonly called adapalene (the product Differine® marketed by Galderma), are widely described and recognized as active ingredients that are as effective as tretinoin for the treatment of acne.
The combination of several local treatments (antibiotics, retinoids, peroxides, zinc) is also used in dermatology to make it possible to enhance the efficacy of the active ingredients and to reduce their toxicity (Cunliffe W. J., J. Dermatol. Treat., 2000, 11 (suppl2), pgs. 13-14).
The multiple application of different dermatological products may be quite cumbersome and demanding for the patient.
Therefore, one must understand the importance of developing a novel treatment that is effective on dermatological conditions in a stable composition offering a good cosmetic property and allowing a single application and a pleasant use for the patient.
Among this range of therapies proposed by one skilled in the art, nothing has encouraged the combination, in the same composition, benzoyl peroxide and a retinoid.
However, the formulation of such a composition poses several problems.
First of all, the efficacy of benzoyl peroxide is linked to its decomposition when it is brought into contact with the skin. Indeed, it is the oxidizing properties of the free radicals produced during this decomposition which lead to the desired effect. Accordingly, to maintain optimum efficacy of the benzoyl peroxide, it is important to prevent its decomposition before administration, that is to say during storage.
Now, benzoyl peroxide is an unstable chemical compound, which makes its formulation in finished products difficult.
The solubility and stability of benzoyl peroxide have been studied by Chellquist et al. in ethanol, propylene glycol and various mixtures of polyethylene glycol 400 (PEG 400) and water (Chellquist E. M. and Gorman W. G., Pharm. Res., 1992, Vol 9: 1341-1346).
Benzoyl peroxide is particularly soluble in PEG 400 and ethanol as the following table shows:
Solubility of benzoylSolventperoxide (mg/g)PEG 40039.6Ethanol17.9Propylene glycol2.95Propylene glycol/water (75:25)0.36Glycerol0.15Water0.000155
This document moreover specifies that the stability of benzoyl peroxide is greatly influenced by the chemical composition of the formulation and by the storage temperature. Benzoyl peroxide is extremely reactive and is degraded in solution at low temperature because of the instability of its peroxide bond.
The authors thus observed that benzoyl peroxide in solution is degraded more or less rapidly in all the solvents studied depending on the type of solvent and its concentration.
The benzoyl peroxide degradation time in PEG 400 (0.5 mg/g), in ethanol and in propylene glycol are respectively 1, 4, 29 and 53 days at 40° C. Such a degradation does not allow the preparation of a product useful for sale.
Thus, to limit the problem of rapid instability of benzoyl peroxide in solution, it was found to be advantageous to formulate the benzoyl peroxide in dispersed form. However, this type of formulation is not completely satisfactory since degradation of benzoyl peroxide is still observed in the finished product.
Another difficulty that has to be overcome for the preparation of a composition comprising both benzoyl peroxide and a retinoid is that most retinoids are particularly sensitive to natural oxidation, to visible light and to ultraviolet radiation, and benzoyl peroxide being a strong oxidant, the chemical compatibility of these compounds in the same formulation poses numerous problems of stability from the physical and chemical point of view.
A study of stability of two retinoids was carried out by combining two commercial products, one containing a retinoid (tretinoin or adapalene) and the second based on benzoyl peroxide (B. Martin et al., Br. J. Dermatol., (1998) 139, (suppl. 52), 8-11).
The presence of the benzoyl peroxide-based formulation causes a very rapid degradation of the oxidation-sensitive retinoids: measurement shows that 50% of the tretinoin is degraded within 2 hours, and 95% within 24 hours. In the composition in which the retinoid is adapalene, no degradation of adapalene was measured for 24 hours. This study confirms that benzoyl peroxide is degraded and degrades oxidation-sensitive retinoids over time by gradually releasing benzoic acid into finished products.
Now, it is clear that the degradation of benzoyl peroxide and of retinoids is not desirable since it damages the efficacy of the composition containing them.
Nothing has encouraged the combination of these two active agents to obtain a stable composition of the emulsion type given that it was commonly known that the presence of benzoyl peroxide chemically and physically destabilized this type of composition.
Furthermore, it was sought to develop compositions which make it possible to enhance the topical penetration of certain active agents by incorporating, into compositions, compounds of the polyurethane polymer type or derivatives thereof (EP-0,299,758). The product Avita®, marketed by BERTEK Pharmaceuticals Inc., is an example thereof. It contains in particular 0.025% by weight of tretinoin, relative to the total weight of the composition, solubilized in compositions of the gel or cream type and containing polyurethane polymers (type 2 polyolprepolymers marketed by Bertek Pharmaceuticals Inc.) to limit desquamation, irritation and drying of the skin.